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These disorders cause an unpleasant fish-like body odour. The problems are psychosocial and management centres on attempting to minimise the odour.

Peroxisomal disorders can be recognized by the presence of dysmorphic features, neurological abnormalities and hepatic and gastrointestinal dysfunction. Widely different features that can occur include the following:

Possibilities for (dietary) treatment are limited.

Eight distinct inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients followed by the demonstration of disease-causing mutations in genes encoding the implicated enzymes. Two of these disorders are due to a defect of the enzyme mevalonate kinase and affect the synthesis of all isoprenoids. Patients with these disorders characteristically present with recurrent episodes of high fever associated with abdominal pain, vomiting and diarrhoea, (cervical) lymphadenopathy, hepatosplenomegaly, arthralgia and skin rash, and may present with additional congenital anomalies.

The remaining six enzyme defects specifically affect the synthesis of cholesterol and involve four autosomal recessive and two X-linked dominant inherited syndromes. Patients afflicted with one of these defects present with multiple congenital and morphogenic anomalies, including internal organ, skeletal and/or skin abnormalities, and/or a marked delay in psychomotor development reflecting cholesterol’s pivotal role in human embryogenesis and development.

Two inborn errors of metabolism affect the modifications of the cholesterol nucleus in both major pathways for bile acid synthesis: -- and -. These disorders produce cholestatic liver disease and malabsorption of fat and fat-soluble vitamins. Onset of symptoms is usually in the first year of life and, untreated, the liver disease can progress to cirrhosis and liver failure. Treatment with chenodeoxycholic acid and cholic acid can lead to dramatic improvement in the liver disease and the malabsorption. Neonatal cholestatic liver disease can also be the presenting feature of two disorders affecting oxidation of the cholesterol side chain — and . However, these disorders more commonly present later with neurological disease. CTX typically presents with cataracts and mental retardation in childhood, followed by motor dysfunction and tendon xanthomata in the second or third decade. Death may be caused by progressive motor dysfunction and dementia or by premature atherosclerosis. Chenodeoxycholic acid has been shown to halt or even reverse neurological dysfunction. α-Methyl-acyl-CoA racemase deficiency can produce a range of neurological problems in adult life including sensory motor neuropathy and pigmentary retinopathy. Other (so far rare) inborn errors of bile acid synthesis include (rapidly progressive neonatal liver disease) a (cholestatic liver disease and fat-soluble vitamin malabsorption), and (adults with hyperlipidaemia and gall stones). In disorders of peroxisome biogenesis and peroxisomal β-oxidation, neurological disease usually predominates; these are considered in 7 ▸ Chap. 40.

Inborn errors exist of the biosynthetic, catabolic, and salvage pathways of purine and pyrimidine metabolism, which are depicted in Fig. 35.1 and 35.3, respectively. The major presenting signs and laboratory findings in these inborn errors are listed in Table 35.1.

is due to a deficiency of the erythroid form of the first enzyme in the heme biosynthetic pathway, 5-aminolevulinic acid synthase. Characteristics of the disease are variable, but typically include adult onset anemia, ineffective erythropoiesis with formation of ring sideroblasts, iron accumulation and pyridoxine responsiveness.

are metabolic disorders due to deficiencies of other enzymes of this pathway, and are associated with striking accumulations and excess excretion of heme pathway intermediates and their oxidized products. Symptoms and signs of the porphyrias are almost all due to effects on the nervous system or skin. The three most common porphyrias, and , differ considerably from each other. The first presents with acute neurovisceral symptoms and can be aggravated by some drugs, hormones and nutritional changes, and is treated with intravenous heme and carbohydrate loading. The skin is affected in the latter two although the lesions are usually distinct and treatment is different. Porphyrias are more often manifest in adults than are most metabolic diseases. All porphyrias are inherited, with the exception of porphyria cutanea tarda, which is due to an acquired enzyme deficiency in liver, although an inherited deficiency is a predisposing factor in some cases.

Two inherited defects in biotin metabolism are known: (HCS) and . Both lead to deficiency of all biotindependent carboxylases, i.e. to (MCD). In HCS deficiency, the binding of biotin to apocarboxylases is impaired. In biotinidase deficiency, biotin depletion ensues from the inability to recycle endogenous biotin and to utilize protein-bound biotin from the diet. As the carboxylases play an essential role in the catabolism of several amino acids, in gluconeogenesis and in fatty-acid synthesis, their deficiency provokes multiple, life-threatening metabolic derangements, eliciting characteristic organic aciduria and neurological symptoms. The clinical presentation is extremely variable in both disorders. Characteristic symptoms include metabolic acidosis, hypotonia, seizures, ataxia, impaired consciousness and cutaneous symptoms, such as skin rash and alopecia. All patients with biotinidase and a majority of patients with HCS deficiency respond dramatically to oral therapy with pharmacological doses of biotin. Delayed diagnosis and treatment in biotinidase deficiency may result in irreversible neurological damage. A few patients with HCS deficiency show a partial or even no response to biotin and seem to have an impaired long-term outcome. , which also causes MCD, is extremely rare. A defect in has been reported in a single child; however the genetic defect remains unresolved to date. (BRBGD) is a recently described subacute encephalopathy which disappears within a few days without neurological sequelae if biotin is administered early.

Sphingolipidoses are a subgroup of lysosomal storage disorders in which sphingolipids accumulate in one or several organs as the result of a primary deficiency in enzymes or activator proteins involved in their degradative pathway. Traditionally, this subgroup also includes Niemann-Pick disease type C, characterized by impaired cellular trafficking of several lipids. With the exception of Fabry disease, which is X-linked recessive, sphingolipidoses have an autosomal recessive inheritance. The clinical presentation and course of the classical forms of the various diseases are often characteristic. With the help of relevant procedures (imaging, neurophysiology, ophthalmologic examination?, careful examination of the patient and perusal of the disease history (especially age and type of first symptom) should lead to a provisional diagnosis and oriented biochemical tests. Late-onset forms are often more difficult to recognize, and foetal presentations have also been overlooked in the past. No overall screening procedure is yet available to date. In most sphingolipidoses, the diagnosis is made by demonstration of the enzymatic defect, generally expressed in most cells, organs or even serum (leukocytes represent the most widely used enzyme source). In specific diseases, more complex biochemical tests or/and a molecular genetics assessment may be necessary. The past 15 years have seen the era of specific therapies for non-neuronopathic Gaucher disease and Fabry disease. But in spite of active research on animal models, knowledge on pathophysiology and progress toward therapy of the neurological forms in human patients remain to date limited.

Genetic defects in enzymes that are involved in the lysosomal degradation of the mucopolysaccharides (glycosaminoglycans, GAGs) (Fig. 39.1) and the oligosaccharide chains of glycoproteins (Fig. 39.8) lead to chronic and progressive storage disorders that share many clinical features. These vary from facial dysmorphism, bone dysplasia (dysostosis multiplex), hepatosplenomegaly, neurological abnormalities, developmental regression and a reduced life expectancy at the severe end of the clinical spectrum, to an almost normal clinical phenotype and life span in patients with more attenuated disease. Mucopolysaccharidoses (MPS) and oligosaccharidoses are transmitted in an autosomal recessive manner, except for the X-linked MPS II (). Diagnosis of these disorders is initially by detecting partially degraded GAG or oligosaccharide in urine and confirmed by specific enzyme assays in serum, leukocytes or skin fibroblasts.

For the majority of disorders treatment is palliative but there have been important advances in the use of specific enzyme replacement therapy strategies for some MPS and this is an area of very rapid development. In addition, haematopoietic stem cell transplantation (HSCT) can improve outcome in carefully selected patients with MPS (especially MPS IH, ), but this procedure is associated with significant morbidity and mortality.

Gene augmentation/transfer using a variety of vectors has been successful in cultured cells and animal models but has not yet been successfully performed in a human patient with one of these disorders.

It is important to remember that prenatal diagnosis is possible for all the MPS and oligosaccharidoses.

Peroxisomal disorders can be recognized by the presence of dysmorphic features, neurological abnormalities and hepatic and gastrointestinal dysfunction. Widely different features that can occur include the following:

Possibilities for (dietary) treatment are limited.